Year: 2020
Type: article
Study design: Observational Study
Abstract: Aims Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods and results We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10−4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvaa161
Authors: Adrien Georges, Juliette Albuisson, Takiy Berrandou, Délia Dupré, Aurélien Lorthioir, Valentina D’Escamard, Antonio F Di Narzo, Daniella Kadian-Dodov, Jeffrey W Olin, Ewa Warchol-Celinska, Aleksander Prejbisz, Andrzej Januszewicz, Patrick Bruneval, Anna A Baranowska, Tom R Webb, Stephen E Hamby, Nilesh J Samani, David Adlam, Natalia Fendrikova-Mahlay, Stanley Hazen, Yu Wang, Min-Lee Yang, Kristina Hunker, Nicolas Combaret, Pascal Motreff, Antoine Chédid, Béatrice Fiquet, Pierre-François Plouin, Elie Mousseaux, Arshid Azarine, Laurence Amar, Michel Azizi, Heather L Gornik, Santhi K Ganesh, Jason C Kovacic, Xavier Jeunemaitre, Nabila Bouatia-Naji
Institutions: Inserm, Université Paris Cité, Paris Cardiovascular Research Center, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Icahn School of Medicine at Mount Sinai, Institute of Cardiology, University of Leicester, NIHR Leicester Biomedical Research Centre, Cleveland Clinic, University of Michigan, Michigan Medicine, Université Clermont Auvergne, Centre Hospitalier Universitaire de Clermont-Ferrand, Case Western Reserve University, Victor Chang Cardiac Research Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,986
Funders: Office of Dietary Supplements, Doris Duke Charitable Foundation, AstraZeneca, Victor Chang Cardiac Research Institute, University of Michigan, Cleveland Clinic, University of Washington, A. Alfred Taubman Medical Research Institute, Arcadia Fund, Australian Government, Georgia Clinical and Translational Science Alliance, National Institute for Health and Care Research, British Heart Foundation, Société Française de Cardiologie, Assistance publique-Hôpitaux de Paris, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Research Resources, National Center for Advancing Translational Sciences, H2020 European Research Council
Awards: Case Western Reserve University/Cleveland Clinic CTSA (UL1), G2444884424, G2504425179, G2622622367, Therapeutic Mechanisms of Cardiac Progenitors in Ischemic Cardiomyopathy, HDL Structure, Function and Dysfunction, G5388388797, Understanding the Molecular Mechanisms of Fibromuscular Dysplasia, Oxidation in Inflammation and Cardiovascular Disease, G5717210089, Training Program in Molecular and Cellular Cardiology, G6123933131, Genetic and Genomic Analysis of Arterial Dysplasia, G6631868199, Toward Therapeutic Manipulation of Endothelial to Mesenchymal Transition, G695633315, Spontaneous coronary artery dissection (SCAD): vascular pathophysiology, epidemiology and genetics, G7499972937, G770776646, Clinical and Translational Science Collaborative of Cleveland, G87592374, G8834083303, G9000011841, G9000022189, G9000269349, G9000275014
OpenAlex ID: W3035401116